Halogenated isopropyl derivatives of ether have demonstrated promise for use in the medical field due to their anesthesia inducing properties. Of these, the most successful to date has been with fluorinated isopropyl ethers such as sevoflurane (fluoromethyl 1,1,1,3,3,3-hexafluro-2-propyl ether). Sevoflurane has demonstrated rapid induction and recovery from anesthesia when administered by inhalation, making it attractive for use as an anesthetic. Further, sevoflurane is a volatile liquid, nonflammable in air at ambient temperatures and has a lower flammability limit in oxygen of about 11.8 volume percent, making it safe to use as well. U.S. Pat. No. 3,683,092 to Regan et al. discloses use of sevoflurane as an anesthetic.
While exhibiting many beneficial anesthetic properties such as the ability to rapidly change depth of anesthesia, use of sevoflurane as a general inhalational anesthetic has been hampered by its potential nephro-toxicity when metabolized at sufficiently high levels. It is however commonly used in Japan.
Attempts to find other halogenated isopropyl derivatives with beneficial anesthetic properties have led scientists to substitute sevoflurane with other similar moieties. These attempts have not been successful in that several related compounds either do not possess any anesthetic properties, produce only small anesthetic properties, or are toxic. For example, U.S. Pat. No. 3,683,092 discloses that the compound CH.sub.3 OCF(CF.sub.3).sub.2 was found to be non-anesthetic up to 8% by volume in oxygen meaning that it would burn at its anesthetic concentration since its lower flammability limit is about 7-8%. Another isomer, trifluoromethyl-2,2,3,3-tetrafluoropropyl ether of Aldrich and Shepard, Jorg., Volume 29, pages 11-15 (1964) has been shown to cause violent convulsions and death in mice at concentrations as low as 0.5%. Yet another isomer, CHF.sub.2 OCH.sub.2 CF.sub.2 CF.sub.3 is non-anesthetic up to its lethal concentration and produces convulsions in mice. Still another comparison, it has been found that the isomeric (CHF.sub.2).sub.2 CF--O--CHF.sub.2 is a weak anesthetic in which deep anesthesia is not obtained and abnormal electro-encephalographic and convulsant activity is observed. Thus it can be seen that there has been little success to date, and a need exists for an anesthetic for use in mammals which will possess the advantageous characteristics of sevoflurane while minimizing the concomitant fluoride ion release.
Another problem that exists with sevoflurane, relates to degradation products when used in a typical anesthetic circuit involving CO.sub.2 absorbants, see Morio, et al "Reaction of Sevoflurane and its Degradation Products with Sodalime: Toxicity of the By-Products", ANESTHESIOLOGY 77:1155-1164, 1992 and Frink et al, "Quantification of the degradation products of sevoflurane in two CO.sub.2 absorbants during low-flow anesthesia in surgical patients" ANESTHESIOLOGY 77:1064-1069, 1992. Although these degradation products eventually include perhaps up to five different compounds, the initial reaction leads to the most prevalent and potentially harmful compound which is known in the art as "Compound A". It is an unsaturated compound of the formula fluromethyl-2, 2 diflouro-1-trifluoromethyl vinyl ether represented as follows: ##STR1##
By way of background, a typical anesthetic circuit includes, of course, the anesthetic machine which administers an inhalational anesthetic to the patient, the patient's respiratory system for inhaling of a mixture of oxygen and anesthetic and exhaling anesthetic mixture now having a high carbon dioxide content, a scrubber system to remove carbon dioxide from the exhaled gas mixture then, of course, a recycle system using one-way valves back to the anesthetic circuit. In this semi-closed loop process, the typical carbon dioxide scrubber or absorbant is a canister of a mixture known generally as sodalime. There are perhaps as many as five commercial manufacturers of sodalime for use in anesthesiology. Generally, those mixtures include a mixture of sodium, calcium and potassium hydroxide. Some examples of sodalime commercially available and commonly used in surgery for CO.sub.2 absorption or scrubbing are SODASORB.TM. by W. R. Grace of Lexington, Mass., Barolyme of Chemtron Medical Division, Allied Health Care Products of St. Louis, Mo., and WAKOLIME.RTM. (Wako Pure Chemical, Osaka, Japan). Sodalime comprises about 5% sodium hydroxide and about 95% calcium hydroxide. Depending upon the manufacturer, other components present in carbon dioxide scrubber canisters include potassium hydroxide, barium hydroxide, sodium silicate, and of course, water. All are very strong bases.
All of these products operate in generally the same way, that is the sodium hydroxide primarily reacts with carbon dioxide, which produces bicarbonate which in turn reacts with the calcium hydroxide to provide insoluble precipitated carbonates. The reaction is exothermic, and although the canister starts at ambient conditions, by the time the surgery is underway it warms and often reaches a stable temperature within the range of 45.degree. C. to 50.degree. C. The exact steady state temperature reached depends upon the CO.sub.2 volume produced by the patient and the total flow of all gases in the air.
As reported in the earlier referenced articles of Morio et al and Frink et al, at elevated temperatures in sodalime, one commonly observes degraded products of sevoflurane which are potentially toxic. In particular there are problems with two different parts of the sevoflurane molecule. The fluoromethoxy carbon portion of the molecule degrades during metabolism in the patient's liver to release fluoride ion which can potentially damage the kidney. The hexafluoroisopropyl portion of the compound, in the presence of sodalime under normal operating conditions, will degrade to provide Compound A, a vinyl unsaturate, which has been demonstrated in the literature to be toxic when inhaled at ranges of from 100 ppm to 1000 ppm during inhalational experiments with rats. Obviously, therefore, although sevoflurane has significant opportunities as an inhalational anesthetic, the organ toxicity issues associated with the use of sevoflurane must first be solved.
In our parent application, Baker et al., Ser. No. 08/010,264, filed Jan. 29, 1993, and entitled DEUTERATED SEVOFLURANE AS AN INHALATIONAL ANESTHETIC, we discovered that deuterated sevoflurane is metabolized and subsequently defluorinated at a much slower rate than sevoflurane itself, thereby reducing fluoride ion release while still maintaining all of the anesthetic properties of sevoflurane. Although this solves a very important problem with this molecule, namely, liver metabolism to release fluoride ion, it does not solve that portion of the problem that relates to degradation products in the presence of CO.sub.2 scrubbers such as sodalime. The present invention represents an improvement on the invention of the parent application and solves the latter sodalime degradation problem. The process may be used with sevoflurane itself or with the deuterated sevoflurane of our parent application.
It is an object of the present invention to provide an improved anesthesia method for use in conjunction with sevoflurane or deuterated sevoflurane as an inhalational anesthetic which will reduce the degradation decomposition of sevoflurane by sodalime scrubbers to the level that release of compound A and other potentially toxic breakdown products of sevoflurane will be trivial and non-toxic.
Yet another object of the present invention is to provide a method for inducing anesthesia in patients involving inhalation of sevoflurane or deuterated sevoflurane but which minimizes or eliminates "Compound A" and/or other degradation products from the anesthetic circuit.
It is yet another object of the present invention to provide a method of inducing anesthesia with sevoflurane which will produce anesthesia in a patient but with a lower organ toxicity risk than normally associated with sevoflurane.
It is a further object of the present invention to provide minimization of degradation products of sevoflurane in a normal anesthetic circuit by controlling the temperature of the carbon dioxide scrubbing canister so that it is at all times at room temperature or lower which, as demonstrated below, minimizes or eliminates the degradation by-products particularly "Compound A".
Further objects of the invention will be demonstrated from the detailed description of the invention which follows.